{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T18:52:41Z","timestamp":1775847161482,"version":"3.50.1"},"reference-count":20,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,6,20]],"date-time":"2016-06-20T00:00:00Z","timestamp":1466380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["BEX 6821\/14\u20106"],"award-info":[{"award-number":["BEX 6821\/14\u20106"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>It is unknown if risk loci, identified by genome\u2010wide association studies of late\u2010onset Alzheimer's disease (LOAD), are linked to common molecular mechanisms through epistatic effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed genome\u2010wide interaction studies of five risk variants for LOAD followed by enrichment analyses to find if there are pathways that simultaneously interact with more than one variant. This novel approach was applied to four independent cohorts (5393 cases and 3746 controls).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found enrichment of epistasis in gonadotropin\u2010releasing hormone signaling with risk single\u2010nucleotide polymorphisms in <jats:italic>APOE<\/jats:italic> and <jats:italic>MS4A6A<\/jats:italic> (<jats:italic>P<\/jats:italic> value\u00a0= 3.7 \u00d7 10<jats:sup>\u22125<\/jats:sup>, <jats:italic>P<\/jats:italic> value = 5.6\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>); vascular smooth muscle contraction pathway was also enriched in epistasis with these loci (<jats:italic>P<\/jats:italic> value\u00a0=\u00a09.6\u00a0\u00d7\u00a010<jats:sup>\u22125<\/jats:sup>, <jats:italic>P<\/jats:italic> value\u00a0=\u00a02.4\u00a0\u00d7\u00a010<jats:sup>\u22127<\/jats:sup>). <jats:italic>MS4A6A<\/jats:italic> risk variant also interacted with dilated cardiomyopathy pathway (<jats:italic>P<\/jats:italic> value\u00a0=\u00a03.1\u00a0\u00d7\u00a010<jats:sup>\u22127<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In addition to <jats:italic>APOE<\/jats:italic>, <jats:italic>MS4A6A<\/jats:italic> polymorphisms should be considered in hormone trials targeting gonadotropins. Interactions of risk variants with neurovascular pathways may also be important in LOAD pathology.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.jalz.2016.05.009","type":"journal-article","created":{"date-parts":[[2016,6,21]],"date-time":"2016-06-21T00:31:40Z","timestamp":1466469100000},"page":"493-497","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["<i>APOE<\/i> and <i>MS4A6A<\/i> interact with GnRH signaling in Alzheimer's disease: Enrichment of epistatic effects"],"prefix":"10.1002","volume":"13","author":[{"given":"Alejandro","family":"C\u00e1ceres","sequence":"first","affiliation":[{"name":"ISGlobal Center for Research in Environmental Epidemiology (CREAL)  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP)  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 E.","family":"Vargas","sequence":"additional","affiliation":[{"name":"CAPES Foundation Ministry of Education of Brazil  Brasilia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan R.","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"ISGlobal Center for Research in Environmental Epidemiology (CREAL)  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP)  Madrid Spain"},{"name":"Department of Mathematics Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,6,20]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2452"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2802"},{"key":"e_1_2_7_4_2","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.neurobiolaging.2007.11.027","article-title":"Epistasis in sporadic Alzheimer's disease","volume":"9","author":"Combarros O","year":"2009","journal-title":"Neurobiol Aging"},{"key":"e_1_2_7_5_2","unstructured":"dBGap. Avaliable at:http:\/\/www.ncbi.nlm.nih.gov\/gap. Accessed: June 21 2016."},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095413"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.803"},{"key":"e_1_2_7_8_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gm249","article-title":"The membrane\u2010spanning 4\u2010domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease","volume":"3","author":"Ant\u00fanez C","year":"2011","journal-title":"Genome Med"},{"key":"e_1_2_7_9_2","unstructured":"AlzGene. Available at:http:\/\/AlzGene.org. Accessed: June 21 2016."},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq324"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1216206110"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.08.002"},{"key":"e_1_2_7_13_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.2174\/187152710793361559","article-title":"Gonadotropin\u2010releasing hormone receptor system: modulatory role in aging and neurodegeneration","volume":"9","author":"Wang L","year":"2010","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2015.05.020"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12143"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2012.147"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1186\/1751-0473-7-10"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-141626"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3114"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2009.913"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1086\/509900"}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1552526016302837?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1552526016302837?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1016\/j.jalz.2016.05.009","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1016\/j.jalz.2016.05.009","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1016\/j.jalz.2016.05.009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T22:31:19Z","timestamp":1759876279000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1016\/j.jalz.2016.05.009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,20]]},"references-count":20,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,4]]}},"alternative-id":["10.1016\/j.jalz.2016.05.009"],"URL":"https:\/\/doi.org\/10.1016\/j.jalz.2016.05.009","archive":["Portico"],"relation":{},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,20]]},"assertion":[{"value":"2016-06-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}